Novel insights into the brain-gut axis: Effects of transcranial direct current stimulation on intestinal barrier function and the enteric nervous system in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is initiated by the infiltration of luminal antigens into the mucosa, which triggers an inappropriate immune response. This inflammatory process results in visceral pain, affecting 62% of IBD patients. The enteric nervous system (ENS), especially the myenteric plexus (MP) as a central structure of the ENS, plays a crucial role in the transmission of visceral pain. Elucidating the interactions of the immune system and the ENS is crucial for developing targeted therapies to treat IBD-caused pain and its chronification. The aims of this work comprise (i) the analysis of immune cell populations infiltrating the MP and (ii) effects elicited on the ENS and the intestine via the brain-gut axis (BGA) by a central application of the neuromodulatory pain treatment transcranial direct current stimulation (tDCS). When investigating immune cell patterns infiltrating the ENS, the infiltrations in MPs Crohn’s disease (CD) patients included macrophages, cytotoxic T cells, and B cells, while ulcerative colitis (UC) MPs were surrounded by periganglionic cytotoxic T cells. Furthermore, the painand inflammation-associated neuropeptide calcitonin gene-related peptide (CGRP) was found to be increased in CD, whereas substance P (SP) was reduced in UC. Moreover, tDCS was investigated, which is a promising candidate for a multimodal treatment for chronic pain in IBD and other chronic pain conditions. In CD patients, tDCS treatment resulted in reduced pain. Furthermore, the barrier function of colonic mucosa was found to be strengthened following tDCS. In addition, tDCS was applied to a murine model of chronic colitis to thoroughly investigate its effects on the functionality of the BGA. After induction of a chronic dextran sodium sulfate (DSS) colitis, tDCS treatment led to an improved intestinal barrier function. Moreover, nociception was reduced by tDCS. Furthermore, mRNA analysis by RNAseq was performed on ENS culture cells. Pathway analysis revealed a shift of enteric glial cells towards a non-inflammatory state, supported by the downregulation proinflammatory genes, such as Gfap, Plp1 and S100B. Interestingly, key components of the IL-1 and NF-κB inflammatory signalling pathways were downregulated, allowing for the hypothesis that tDCS is modulating an inflammatory state within glial cells. Other significantly downregulated pathways include chemotaxis, extracellular matrix organization, as well as pain-related pathways. In conclusion, these novel insights on ENS structures in inflammation and the functionality of the BGA hold potential to advance our understanding in MPs in chronic intestinal inflammation and their transcriptional regulation.